tbuckley/cabot-search huggingface dataset:
Intracytoplasmic sperm injection induces transgenerational abnormalities in mice
Authors: Mito Kanatsu-Shinohara, Yusuke Shiromoto, Narumi Ogonuki, Kimiko Inoue, Satoko Hattori, Kento Miura, Naomi Watanabe, Ayumi Hasegawa, Keiji Mochida, Takuya Yamamoto, Tsuyoshi Miyakawa, Atsuo Ogura, Takashi Shinohara
Journal: Journal of Clinical Investigation (2023)

In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are 2 major assisted reproductive techniques (ARTs) used widely to treat infertility. Recently, spermatogonial transplantation emerged as a new ART to restore fertility to young patients with cancer after cancer therapy. To examine the influence of germ cell manipulation on behavior of offspring, we produced F1 offspring by a combination of two ARTs, spermatogonial transplantation and ICSI. When these animals were compared with F1 offspring produced by ICSI using fresh wild-type sperm, not only spermatogonial transplantation–ICSI mice but also ICSI-only control mice exhibited behavioral abnormalities, which persisted in the F2 generation. Furthermore, although these F1 offspring appeared normal, F2 offspring produced by IVF using F1 sperm and wild-type oocytes showed various types of congenital abnormalities, including anophthalmia, hydrocephalus, and missing limbs. Therefore, ARTs can induce morphological and functional defects in mice, some of which become evident only after germline transmission.
Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas
Authors: C. Ryan Miller, Anita B. Hjelmeland
Journal: Journal of Clinical Investigation (2023)

Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow–derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti–IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.
Dietary branched-chain amino acids get to the heart of H3K23Pr
Authors: Christina Demetriadou, Daniel S. Kantner, Nathaniel W. Snyder
Journal: Journal of Clinical Investigation (2023)

Cardiac metabolism provides effects that extend beyond the transformation of energy for the heart to operate effectively. Some metabolites also function as signaling molecules and exert transcriptional changes. Heart failure is a progressive pathology in which these metabolite functions falter. In this issue of the JCI, Yang et al. describe a protective effect from a low–branched chain amino acid (BCAA) diet in a mouse model of heart failure. The findings implicate a propionylation mark on histone H3 lysine 23 (H3K23Pr), previously shown to be dependent on the BCAA isoleucine, in transcriptional control of the cardiac stress response. The result underscores the interplay between metabolism and histone acylation, highlighting targeted dietary and pharmacological intervention as a means to decelerate cardiac hypertrophy.
FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters
Authors: Mengjiao Li, Tatsunori Nishimura, Yasuto Takeuchi, Tsunaki Hongu, Yuming Wang, Daisuke Shiokawa, Kang Wang, Haruka Hirose, Asako Sasahara, Masao Yano, Satoko Ishikawa, Masafumi Inokuchi, Tetsuo Ota, Masahiko Tanabe, Kei-ichiro Tada, Tetsu Akiyama, Xi Cheng, Chia-Chi Liu, Toshinari Yamashita, Sumio Sugano, Yutaro Uchida, Tomoki Chiba, Hiroshi Asahara, Masahiro Nakagawa, Shinya Sato, Yohei Miyagi, Teppei Shimamura, Luis Augusto E. Nagai, Akinori Kanai, Manami Katoh, Seitaro Nomura, Ryuichiro Nakato, Yutaka Suzuki, Arinobu Tojo, Dominic C. Voon, Seishi Ogawa, Koji Okamoto, Theodoros Foukakis, Noriko Gotoh
Journal: Journal of Clinical Investigation (2023)

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.
Antitumor activity of AZD0754, a dnTGFβRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer
Authors: Peter Zanvit, Dewald van Dyk, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica M. Pezold, John Meekin, Chien-ying Chang, Rosa A. Carrasco, Shannon Breen, Crystal Sao-Fong Cheung, Ariel Endlich-Frazier, Benjamin Clark, Nina J. Chu, Alessio Vantellini, Philip L. Martin, Clare E. Hoover, Kenesha Riley, Steve M. Sweet, David Chain, Yeoun Jin Kim, Eric Tu, Nathalie Harder, Sandrina Phipps, Melissa Damschroder, Ryan N. Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco
Journal: Journal of Clinical Investigation (2023)

Prostate cancer is generally considered an immunologically "cold" tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to "heat up" the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-β type II receptor, bolstering its activity in the TGF-β–rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-β–rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line–derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.
“Stuck in the Middle with You”: intermediate cell states are not always in transition
Authors: Jennifer M.S. Sucre, A. Scott McCall, Jonathan A. Kropski
Journal: Journal of Clinical Investigation (2023)

The era of single-cell multiomics has led to the identification of lung epithelial cells with features of both alveolar type 1 (AT1) and alveolar type 2 (AT2) pneumocytes, leading many to infer that these cells are a distinct cell type in the process of transitioning between AT2 and AT1 cells. In this issue of the JCI, Wang and colleagues demonstrated that many so-called "transitional cells" do not actually contribute to functional repair. The findings warrant a reimagining of these cells as existing in a nondirectional, intermediate cell state, rather than moving through a transitory process from one cell type to another. We look forward to further exploration of diverse cell state expression profiles and a more refined examination of hallmark gene function beyond population labeling.
Considering Diversity in Pulmonary Function Testing
Authors: Aparna Balasubramanian, Loretta Que, A. Ian Wong, Sanja Stanojevic, Meredith McCormack
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Considering Diversity in Pulmonary Function Testing." American Journal of Respiratory and Critical Care Medicine, 208(10), pp. P1–P2
The LMIT: Light-mediated minimally-invasive theranostics in oncology
Authors: Yingwei Fan, Shuai Liu, Enze Gao, Rui Guo, Guozhao Dong, Yangxi Li, Tianxin Gao, Xiaoying Tang, Hongen Liao
Journal: Theranostics (2023)

Minimally-invasive diagnosis and therapy have gradually become the trend and research hotspot of current medical applications.The integration of intraoperative diagnosis and treatment is a development important direction for real-time detection, minimally-invasive diagnosis and therapy to reduce mortality and improve the quality of life of patients, so called minimally-invasive theranostics (MIT).Light is an important theranostic tool for the treatment of cancerous tissues.Light-mediated minimally-invasive theranostics (LMIT) is a novel evolutionary technology that integrates diagnosis and therapeutics for the less invasive treatment of diseased tissues.Intelligent theranostics would promote precision surgery based on the optical characterization of cancerous tissues.Furthermore, MIT also requires the assistance of smart medical devices or robots.And, optical multimodality lay a solid foundation for intelligent MIT.In this review, we summarize the important state-of-the-arts of optical MIT or LMIT in oncology.Multimodal optical image-guided intelligent treatment is another focus.Intraoperative imaging and real-time analysis-guided optical treatment are also systemically discussed.Finally, the potential challenges and future perspectives of intelligent optical MIT are discussed.
In situ theranostic platform combining highly localized magnetic fluid hyperthermia, magnetic particle imaging, and thermometry in 3D
Authors: Oliver Buchholz, Kulthisa Sajjamark, Jochen Franke, Huimin Wei, André Behrends, Christian Münkel, Cordula Grüttner, Pierre Levan, Dominik von Elverfeldt, Matthias Graeser, Thorsten Buzug, Sébastien Bär, Ulrich G. Hofmann
Journal: Theranostics (2023)

Theranostic platforms, combining diagnostic and therapeutic approaches within one system, have garnered interest in augmenting invasive surgical, chemical, and ionizing interventions. Magnetic particle imaging (MPI) offers a quite recent alternative to established radiation-based diagnostic modalities with its versatile tracer material (superparamagnetic iron oxide nanoparticles, SPION). It also offers a bimodal theranostic framework that can combine tomographic imaging with therapeutic techniques using the very same SPION.
Reprogramming Exosomes to Escape from Immune Surveillance for Mitochondrial Protection in Hepatic Ischemia-Reperfusion Injury
Authors: Shanshan Liu, Xinyu Xiao, La Zhang, Jianwei Wang, Wei Zhao, Haichuan Liu, Rui Liao, Zhi Li, Mengxia Xu, Jiao Guo, Baoyong Zhou, Chengyou Du, Qiling Peng, Ning Jiang
Journal: Theranostics (2023)

Background: Therapeutic interventions such as synthetic drugs and microRNA (miR) modulators have created opportunities for mitigating hepatic ischemia/reperfusion injury (HIRI) by alleviating mitochondrial dysfunction.However, delivering multi-therapeutic ingredients with low toxicity to hepatocytes still lags behind its development.Methods: In this study, we endowed exosomes with delivery function to concentrate on hepatocytes for multidimensionally halting mitochondria dysfunction during HIRI.Concretely, exosomes were reprogrammed with a transmembrane protein CD47, which acted as a "camouflage cloak" to mimic the "don't eat me" mechanism to escape from immune surveillance.Besides, HuR was engineered bridging to the membrane by fusing with CD47 and located in the cytoplasm for miR loading.Results: This strategy successfully delivered dual payloads to hepatocytes and efficiently protected mitochondria by inhibiting the opening of mitochondrial permeability transition pore (mPTP) and upregulating mitochondrial transcription factor A (TFAM), respectively.Conclusions: The reprogramming of exosomes with CD47 and HuR for targeted delivery of CsA and miR inhibitors represents a promising therapeutic strategy for addressing HIRI.This approach shows potential for safe and effective clinical applications in the treatment of HIRI.
Inactivation of ERK1/2 signaling mediates dysfunction of basal meningeal lymphatic vessels in experimental subdural hematoma
Authors: Jiangyuan Yuan, Xuanhui Liu, Meng Nie, Yupeng Chen, Mingqi Liu, Jinhao Huang, Weiwei Jiang, Chuang Gao, Wei Quan, Zhitao Gong, Tangtang Xiang, Xinjie Zhang, Zhuang Sha, Chenrui Wu, Dong Wang, Shenghui Li, Jianning Zhang, Rongcai Jiang
Journal: Theranostics (2023)

Rationale: Meningeal lymphatic vessels (MLVs) are essential for the clearance of subdural hematoma (SDH).However, SDH impairs their drainage function, and the pathogenesis remains unclear.Herein, we aimed to understand the pathological mechanisms of MLV dysfunction following SDH and to test whether atorvastatin, an effective drug for SDH clearance, improves meningeal lymphatic drainage (MLD).Methods: We induced SDH models in rats by injecting autologous blood into the subdural space and evaluated MLD using Gadopentetate D, Evans blue, and CFSE-labeled erythrocytes.Whole-mount immunofluorescence and transmission electron microscopy were utilized to detect the morphology of MLVs.Phosphoproteomics, western blot, flow cytometry, and in vitro experiments were performed to investigate the molecular mechanisms underlying dysfunctional MLVs.Results: The basal MLVs were detected to have abundant valves and play an important role in draining subdural substances.Following SDH, these basal MLVs exhibited disrupted endothelial junctions and dilated lumen, leading to impaired MLD.Subsequent proteomics analysis of the meninges detected numerous dephosphorylated proteins, primarily enriched in the adherens junction, including significant dephosphorylation of ERK1/2 within the meningeal lymphatic endothelial cells (LECs).Subdural injection of the ERK1/2 kinase inhibitor PD98059 resulted in dilated basal MLVs and impaired MLD, resembling the dysfunctional MLVs observed in SDH.Moreover, inhibiting ERK1/2 signaling severely disrupted intercellular junctions between cultured LECs.Finally, atorvastatin was revealed to protect the structure of basal MLVs and accelerate MLD following SDH.However, these beneficial effects of atorvastatin were abolished when combined with PD98059. Conclusion:Our findings demonstrate that SDH induces ERK1/2 dephosphorylation in meningeal LECs, leading to disrupted basal MLVs and impaired MLD.Additionally, we reveal a beneficial effect of atorvastatin in improving MLD.
Neutrophil-like pH-responsive pro-efferocytic nanoparticles improve neurological recovery by promoting erythrophagocytosis after intracerebral hemorrhage
Authors: Linfeng Fan, Lulu Jin, Tianchi Tang, Yonghe Zheng, Zihang Chen, Haopu Lin, Chao Ding, Tingting Wang, Huaijun Chen, Yinghan Guo, Chaoran Xu, Hang Zhou, Xinyan Wu, Xiongjie Fu, Feng Yan, Zhengwei Mao, Gao Chen
Journal: Theranostics (2023)

Rationale: Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease resulting from blood extravasating into the brain parenchyma.Escalation of erythrophagocytosis (a form of efferocytosis), avoiding the consequent release of the detrimental erythrocyte lysates, may be a promising target of ICH management.The ADAM17 inhibitor and liver X receptor (LXR) agonist could promote efficient efferocytosis and injury repair.Nevertheless, the poor bioavailability and restriction of the blood-brain barrier (BBB) hinder their application.Therefore, it is needed that biocompatible and smart nanoplatforms were designed and synthesized to realize effective therapy targeting erythrophagocytosis.Methods: We first assessed the synergistic effect of therapeutic GW280264X (an ADAM17 inhibitor) and desmosterol (an LXR agonist) on erythrophagocytosis in vitro.Then a pH-responsive neutrophil membrane-based nanoplatform (NPEOz) served as a carrier to accurately deliver therapeutic GW280264X and desmosterol to the damaged brain was prepared via co-extrusion.Afterwards, their pH-responsive performance was valued in vitro and targeting ability was assessed through fluorescence image in vivo.Finally, the pro-erythrophagocytic and anti-neuroinflammatory ability of the nanomedicine and related mechanisms were investigated.Results: After the synergistical effect of the above two drugs on erythrophagocytosis was confirmed, we successfully developed neutrophil-disguised pH-responsive nanoparticles to efficiently co-deliver them.The nanoparticles could responsively release therapeutic agents under acidic environments, and elicit favorable biocompatibility and ability of targeting injury sites.D&G@NPEOz nanoparticles enhanced erythrophagocytosis through inhibiting shedding of the efferocytotic receptors MERTK/AXL mediated by ADAM17 and accelerating ABCA-1/ABCG-1-mediated cholesterol efflux regulated by LXR respectively.In addition, the nano-formulation was able to modulate the inflammatory microenvironment by transforming efferocytes towards a therapeutic phenotype with reducing the release of proinflammatory cytokines while increasing the secretion of anti-inflammatory factors, and improve neurological function.Conclusions: This biomimetic nanomedicine is envisaged to offer an encouraging strategy to effectively promote hematoma and inflammation resolution, consequently alleviate ICH progression.
Regulatory mechanisms of circular RNAs during human mesenchymal stem cell osteogenic differentiation
Authors: Chiara Mazziotta, Giada Badiale, Christian Felice Cervellera, Mauro Tognon, Fernanda Martini, John Charles Rotondo
Journal: Theranostics (2023)

Human osteogenic differentiation is a complex and well-orchestrated process which involves a plethora of molecular players and cellular processes.A growing number of studies have underlined that circular RNAs (circRNAs) play an important regulatory role during human osteogenic differentiation.CircRNAs are single-stranded, covalently closed non-coding RNA molecules that are acquiring increased attention as epigenetic regulators of gene expression.Given their intrinsic high conformational stability, abundance, and specificity, circRNAs can undertake various biological activities in order to regulate multiple cellular processes, including osteogenic differentiation.The most recent evidence indicates that circRNAs control human osteogenesis by preventing the inhibitory activity of miRNAs on their downstream target genes, using a competitive endogenous RNA mechanism.The aim of this review is to draw attention to the currently known regulatory mechanisms of circRNAs during human osteogenic differentiation.Specifically, we provide an understanding of recent advances in research conducted on various human mesenchymal stem cell types that underlined the importance of circRNAs in regulating osteogenesis.A comprehensive understanding of the underlying regulatory mechanisms of circRNA in osteogenesis will improve knowledge on the molecular processes of bone growth, resulting in the potential development of novel preclinical and clinical studies and the discovery of novel diagnostic and therapeutic tools for bone disorders.
Fibroblast-derived extracellular vesicles as trackable efficient transporters of an experimental nanodrug with fibrotic heart and lung targeting
Authors: Jorge RuizdelRio, Gabriela Guedes, Danielle Novillo, Elena Lecue, Ana Palanca, Aitziber L. Cortajarena, Ana V. Villar
Journal: Theranostics (2023)

The discovery of extracellular vesicles (EVs) as efficient exogenous biotransporters of therapeutic agents into cells across biological membranes is an exciting emerging field.Especially the potential of EVs as targeted delivery systems for diseases with selective treatments, such as fibrosis, whose treatment causes side effects in other organs not involved in the disease.Methods: In this study, we collected embryonic fibroblast-derived EVs from two different centrifugation fractions, 10 K g and 100 K g fractions from a NIH-3T3 cell line loaded with an experimental drug.Mice with fibrotic hearts and lungs were obtained by administration of angiotensin II.We generated fluorescent EVs and bioluminescent drug to observe their accumulation by colocalization of their signals in fibrotic heart and lung.The biodistribution of the drug in various organs was obtained by detecting the Au present in the drug nanostructure.Results: The drug-loaded EVs successfully reduced fibrosis in pathological fibroblasts in vitro, and modified the biodistribution of the experimental drug, enabling it to reach the target organs in vivo.We described the pre-analytical characteristics of EVs related to physical variables, culture and harvesting conditions, crucial for their in vivo application as nanotransporters using a previously validated protein-based antifibrotic drug.The results showed the colocalization of EVs and the experimental drug in vivo and ex vivo and the efficient reduction of fibrosis in vitro.This work demonstrates that 10K-EVs and 100K-EVs derived from fibroblasts can act as effective biotransporters for targeted drug delivery to profibrotic fibroblasts, lungs, or heart. Conclusion:We observed that fibroblast-derived 10K-EVs and 100K-EVs are useful biotransporters encapsulating a new generation drug leading to a reduction of fibrosis in profibrotic fibroblasts in vitro.In addition, drug containing EVs were shown to reach fibrotic heart and lungs in vivo, enhancing free drug biodistribution.
Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy
Authors: Dongdong Tang, Yang Yan, Yangyang Li, Yuqing Li, Junqiang Tian, Li Yang, Hui Ding, Ghassan Bashir, Houhong Zhou, Qiuxia Ding, Ran Tao, Shaohua Zhang, Zhiping Wang, Song Wu
Journal: Theranostics (2023)

Intravesical chemotherapy is highly recommended after transurethral resection of bladder tumor for patients with bladder cancer (BCa). However, this localized adjuvant therapy has drawbacks of causing indiscriminate damage and inability to penetrate bladder mucosal.
Peptide receptor radionuclide therapy (PRRT) in metastatic neuroendocrine tumors of unknown primary (CUP-NETs)
Authors: Richard P. Baum, Peipei Wang, Vivianne Jakobsson, Tianzhi Zhao, Christiane Schuchardt, Pek-Lan Khong, Jingjing Zhang
Journal: Theranostics (2023)

Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumors (NETs) has been explored for more than two decades, but there are only limited data on the treatment of NETs of unknown primary site (CUP-NETs). This study aimed to analyze the long-term outcome, efficacy, and safety of PRRT in patients with CUP-NETs.